WISP-1 positively regulates angiogenesis by controlling VEGF-A expression in human osteosarcoma

• Published in: Cell death & disease 2017-04, Vol.8 (4), p.e2750-e2750
• Main Authors: Tsai, Hsiao-Chi, Tzeng, Huey-En, Huang, Chun-Yin, Huang, Yuan-Li, Tsai, Chun-Hao, Wang, Shih-Wei, Wang, Po-Chuan, Chang, An-Chen, Fong, Yi-Chin, Tang, Chih-Hsin
• Format: Article
• Language: English
• Subjects: 13; 13/21; 13/51; 13/95; 14; 38; 38/77; 631/337/384/331; 631/80/86; 64; 692/4019/592/16; 692/699/67/1344; 82; Adolescent; Adult; Angiogenesis; Animals; Antibodies; Biochemistry; Biomedical and Life Sciences; Bone Neoplasms - blood supply; Bone Neoplasms - metabolism; Bone Neoplasms - pathology; CCN Intercellular Signaling Proteins - metabolism; Cell Biology; Cell Culture; Cell Line, Tumor; Chick Embryo; Children & youth; Endothelial Cells - metabolism; Endothelial Cells - pathology; Female; Gene expression; Gene Expression Regulation, Neoplastic; Humans; Immunology; Life Sciences; Male; MicroRNAs - biosynthesis; Neovascularization, Pathologic - metabolism; Neovascularization, Pathologic - pathology; Original; original-article; Osteosarcoma - blood supply; Osteosarcoma - metabolism; Osteosarcoma - pathology; Proto-Oncogene Proteins - metabolism; RNA, Neoplasm - biosynthesis; Signal Transduction; Stem Cells - metabolism; Stem Cells - pathology; Vascular Endothelial Growth Factor A - biosynthesis; Young adults
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2016.421

In recent years, much research has focused on the role of angiogenesis in osteosarcoma, which occurs predominantly in adolescents and young adults. The vascular endothelial growth factor-A (VEGF-A) pathway is the key regulator of angiogenesis and in osteosarcoma. VEGF-A expression has been recognized as a prognostic marker in angiogenesis. Aberrant WNT1-inducible signaling pathway protein-1 (WISP-1) expression is associated with various cancers. However, the function of WISP-1 in osteosarcoma angiogenesis is poorly understood. We demonstrate a positive correlation between WISP-1 and VEGF-A expression in human osteosarcoma. Moreover, we show that WISP-1 promotes VEGF-A expression in human osteosarcoma cells, subsequently inducing human endothelial progenitor cell (EPC) migration and tube formation. The focal adhesion kinase (FAK), Jun amino-terminal kinase (JNK), and hypoxia-inducible factor (HIF)-1 α signaling pathways were activated after WISP-1 stimulation, while FAK, JNK, and HIF-1 α inhibitors or small interfering RNA (siRNA) abolished WISP-1-induced VEGF-A expression and angiogenesis. In vitro and in vivo studies revealed down-regulation of microRNA-381 (miR-381) in WISP-1-induced VEGF-A expression and angiogenesis. Our findings reveal that WISP-1 enhances VEGF-A expression and angiogenesis through the FAK/JNK/HIF-1 α signaling pathways, as well as via down-regulation of miR-381 expression. WISP-1 may be a promising target in osteosarcoma angiogenesis.